Integrins are a superfamily of cell adhesion receptors, which are transmembrane glycoproteins expressed on a variety of cells. These cell surface adhesion receptors include gpIIb /IIIa, the fibrinogen receptor, and .alpha..sub.v.beta..sub.3, the vitronectin receptor. The fibrinogen receptor gpIIb/IIIa is expressed on the platelet surface and it mediates platelet aggregation and the formation of a hemostatic clot at the site of a bleeding wound. Philips, et al., Blood., 1988, 71, 831. The vitronectin receptor (.alpha..sub.v.beta..sub.3 is expressed on a number of cells, including endothelial, smooth muscle, osteoclast, and tumor cells, and, thus, it has a variety of functions. The .alpha..sub.v.beta..sub.3 receptor expressed on the membrane of osteoclast cells mediates the bone resportion process and contributes to the development of osteoporosis. Ross, et al., J. Biol. Chem., 1987, 262, 7703. The .alpha..sub.v.beta..sub.3 receptor expressed on human aortic smooth muscle cells stimulates their migration into neointima, which leads to the formation of atherosclerosis and restenosis after angioplasty. Brown, et al., Cardiovascular Res., 1994, 28, 1815. Additionally, a recent study has shown that a .alpha..sub.v.beta..sub.3 antagonist is able to promote tumor regression by inducing apoptosis of angiogenic blood vessels. Brooks, et al., Cell, 1994, 79, 1157. Thus, agents that would block the vitronectin receptor would be useful in treating diseases mediated by this receptor, such as osteoporosis, atherosclerosis, restenosis and cancer.
The vitronectin receptor is known to bind to bone matrix proteins, such as osteopontin, bone sialoprotein and thrombospondin, which contain the tri-peptide Arg-Gly-Asp (or RGD) motif. Thus, Horton, et al., Exp. Cell Res. 1991, 195, 368, disclose that RGD-containing peptides and an anti-vitronectin receptor antibody (23C6) inhibit dentine resorption and cell spreading by osteoclasts. In addition, Sato, et al., J. Cell Biol. 1990, 111, 1713 disclose that echistatin, a snake venom peptide which contains the RGD sequence, is a potent inhibitor of bone resorption in tissue culture, and inhibits attachment of osteoclasts to bone. Fisher, et al., Endocrinology 1993, 132, 1411, has further shown that echistatin inhibits bone resorption in vivo in the rat. Bertolini et al., J. Bone Min. Res., 6, Sup. 1, S146, 252 have shown that cylco-S,S-N.sup..alpha. -acetyl-cysteinyl-N.sup..alpha. -methyl-argininyl-glycyl-aspartyl-penicillamine inhibits osteoclast attachment to bone. EP 528 587 and 528 586 report substituted phenyl derivatives which inhibit osteoclast mediated bone resorption.
Alig et al., EP 0 381 033, Hartman, et al., EP 0 540,334, Blackburn, et al., WO 93/08174, Bondinell, et al., WO 93/00095, Blackburn, et al. WO 95104057, Egbertson, et al, EP 0 478 328, Sugihara, et al. EP 529,858, Porter, et al., EP 0 542 363, and Fisher, et al., EP 0 635 492 disclose certain compounds that are useful for inhibiting the fibrinogen receptor. It has now been discovered that certain compounds are potent inhibitors of the vitronectin receptor. In particular, it has been discovered that such compounds are more potent inhibitors of the vitronectin receptor than the fibrinogen receptor.